Dihydro-1,3,5-triazine amine derivatives and their therapeutic uses

ABSTRACT

The invention concerns compounds of general formula (I) wherein: R1, R2, R3, R4, R5 and R6 are as defined in Claim 1. Said compounds are useful in the treatment of pathologies related to the insulin-resistance syndrome.

The present invention relates to amine-containing derivatives ofdihydro-1,3,5-triazine which are useful in the treatment of pathologicalconditions associated with the insulin-resistance syndrome.

Amine-containing derivatives of dihydro-1,3,5-triazine havinghypoglycaemic properties have been described in JP-A-73 64 088 andJP-A-79 14 986.

The aim of the present invention is to provide novel compounds havingimproved properties.

The subject of the present invention is thus a compound of generalformula (I):

in which:

-   R1, R2, R3 and R4 are chosen independently from the groups:    -   H,    -   (C1-C20)alkyl substituted or otherwise with halogen,        (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C8)cycloalkyl,    -   (C2-C20)alkylene substituted or otherwise with halogen,        (C1-C5)alkyl, (C1-C5)alkoxy,    -   (C2-C20)alkyne substituted or otherwise with halogen,        (C1-C5)alkyl, (C1-C5)alkoxy,    -   (C3-C8)cycloalkyl substituted or otherwise with (C1-C5)alkyl,        (C1-C5)alkoxy,    -   (C3-C8)heterocycloalkyl carrying one or more heteroatoms chosen        from N, O, S and substituted or otherwise with (C1-C5)alkyl,        (C1-C5)alkoxy,    -   (C6-C14)aryl (C1-C20)alkyl substituted or otherwise with amino,        hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,        (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,        (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,        carboxymethyl or carboxyethyl,    -   (C6-C14)aryl substituted or otherwise with amino, hydroxyl,        thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl (C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C1-C13)heteroaryl carrying one or more heteroatoms chosen from        N, O, S and substituted or otherwise with amino, hydroxyl, thio,        halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

it being possible for R1 and R2, on the one hand, and R3 and R4, on theother hand, to form with the nitrogen atom an n-membered ring (n between3 and 8) comprising or otherwise one or more heteroatoms chosen from N,O, S and being capable of being substituted with one or more of thefollowing groups: amino, hydroxyl, thio, halogen, (C1-C5)alkyl,(C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl (C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl,

-   R5 and R6 are chosen independently from the groups:    -   H,    -   (C1-C20)alkyl substituted or otherwise with amino, hydroxyl,        thio, halogen, (C1-C5) alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C2-C20)alkylene substituted or otherwise with amino, hydroxyl,        thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C2-C20)alkyne substituted or otherwise with amino, hydroxyl,        thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C3-C8)cycloalkyl substituted or otherwise with amino, hydroxyl,        thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C3-C8)heterocycloalkyl carrying one or more heteroatoms chosen        from N, O, S and substituted or otherwise with amino, hydroxyl,        thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C6-C14)aryl substituted or otherwise with amino, hydroxyl,        thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C1-C13)heteroaryl carrying one or more heteroatoms chosen from        N, O, S and substituted or otherwise with amino, hydroxyl, thio,        halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C6-C14)aryl(C1-C5)alkyl substituted or otherwise with amino,        hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,        (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,        (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,        carboxymethyl or carboxyethyl,

it being possible for R5 and R6 to form with the carbon atom to whichthey are attached an m-membered ring (m between 3 and 8) comprising orotherwise one or more heteroatoms chosen from N, O, S and being capableof being substituted with amino, hydroxyl, thio, halogen, (C1-C5)alkyl,(C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl, or being capable of forming with thecarbon atom a C10-C30 polycyclic residue substituted or otherwise withamino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,(C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl,

it being possible for the nitrogen atom of a heterocycloalkyl orheteroaryl group to be substituted with a (C1-C5)alkyl,(C3-C8)cycloalkyl, (C6-C14)aryl, (C6-C14)aryl(C1-C5)alkyl or (C1-C6)acylgroup,

with the exclusion of the compounds of formula I in which:

a—R1=H, R2=H, R3=H, R5=CH3, R6=CH3 and R4=phenethyl, phenoxyethyl,2-phenylthioisopropyl or benzyl;

b—R1=H, R2=H, R3=H or CH3, R4=H, methyl, butyl or phenethyl, R5=H orethyl and R6 is 3-methyl-5-isoxazolyl, 5-methyl-3-isoxazolyl,3-methyl-5-pyrazolyl or (5-methyl-3-isoxazolyl)methyl,

c—R1, R2, R3 and R4 represent a hydrogen atom, as well as thetautomeric, enantiomeric, diastereoisomeric and epimeric forms and thepharmaceutically acceptable salts.

The expression m-membered ring formed by R5 and R6 is understood to meanin particular a saturated ring such as a cyclohexyl, piperidinyl ortetrahydropyranyl group.

The expression polycyclic group formed by R5 and R6 is understood tomean an optionally substituted carbon-containing polycyclic group and inparticular a steroid residue.

A particular group of compounds of formula (I) is that in which R5 ishydrogen.

Another particular group of compounds of formula (I) is that in which R5and R6 form with the carbon atom to which they are attached anm-membered ring (m between 3 and 8) comprising or otherwise one or moreheteroatoms chosen from N, O, S and being capable of being substitutedwith one or more of the following groups: (C1-C5)alkyl, amino, hydroxyl,(C1-C5)alkylamino, (C1-C5)alkoxy, (C1-C5)alkylthio, (C6-C14)aryl,(C6-C14)aryl(C1-C5)alkoxy,

or form with the carbon atom a C10-C30 polycyclic residue substituted orotherwise with amino, hydroxyl, thio, halogen, (C1-C5)alkyl,(C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl.

Another particular group of compounds of formula (I) is that in which R5and R6 are chosen independently from the groups:

-   -   (C1-C20)alkyl substituted or otherwise with amino, hydroxyl,        thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl.

A more particular group of compounds of formula (I) is that in which R1and R2 are chosen independently from the groups specified above with theexception of the hydrogen atom and R3 and R4 represent a hydrogen. Moreparticularly, a preferred group of compounds of formula (I) is that inwhich R1 and R2 are an alkyl, advantageously methyl, group and R3 and R4represent a hydrogen.

The invention also relates to the tautomeric, enantiomeric,diastereoisomeric and epimeric forms of the compounds of general formula(I).

The compounds of general formula (I) possess basic nitrogen atoms whichmay be monosalified or disalified with organic or inorganic acids.

The compounds of general formula (I) may be prepared by reacting acompound of general formula (II)

in which R1, R2, R3 and R4 are as defined above, with a compound ofgeneral formula (III), (IV) or (V)

in which R5 and R6 are as defined above and R7 is a methyl or ethylgroup, in a polar solvent (for example ethanol or dimethylformamide) inthe presence of an organic acid (for example camphorsulphonic acid) orof an inorganic acid (for example hydrochloric acid).

The compounds of general formula (II) are biguanides whose synthesis isroutine to every person skilled in the art. We will cite for examplesome publications describing the synthesis of such compounds (FR1537604, FR 2132396; K. H. Slotta and R. Tschesche, Ber., 1929 (62b),1398; S. L. Shapiro, V. A. Parrino, E. Rogow and L. Freedman, J. Org.Chem., 1959 (81), 3725; S. L. Shapiro, V. A. Parrino and L. Freedman, J.Org. Chem., 1959 (81), 3728; S. L. Shapiro, V. A. Parrino and L.Freedman, J. Org. Chem., 1959 (81), 4636).

The compounds according to the present invention are useful in thetreatment of pathological conditions associated with theinsulin-resistance syndrome (X syndrome).

Insulin-resistance is characterized by a reduction in the action ofinsulin (cf. Presse Médicale, 1997, 26 (No. 14), 671-677) and isinvolved in a large number of pathological states, such as diabetes andmore particularly non-insulin-dependent diabetes (type II diabetes orNIDDM), dyslatupidaemia, obesity, high blood pressure, as well ascertain microvascular and macrovascular complications such asatherosclerosis, retinopathies and neuropathies.

In this regard, reference may be made for example to Diabètes, vol. 37,1988, 1595-1607; Journal of Diabetes and its complications, 1998, 12,110-119 or Horm. Res., 1992, 38, 28-32.

In particular, the compounds of the invention have a high hypoglycaemicactivity.

The compounds according to the present invention can also be used totreat chronic complications which are in particular due to the formationof “advanced glycosylation end-products” noted AGEs which are derivedfrom the glycoxidation reaction between glucose, its oxidationderivatives and the amino functional groups of proteins, including theso-called Maillard reactions for glycation of glyoxal for example.

Indeed, recently published data clearly show the impact of AGEs on renalcomplications (Nephr. Dial. Transplant., 2000, 15 (suppl 2), 7-11), onatherosclerosis, Alzheimer's disease and other neurodegenerativediseases (Glycoconj. J., 1998, 15 (10), 1039-42; Brain Res., 2001,888(2), 256). The formation of AGE may also play an important part inthe pathogenesis of angiopathy, in particular in diabetics, and also insenility (J. Neuropathol. Exp. Neurol., 2000, 59 (12), 1094).

The subject of the present invention is therefore also pharmaceuticalcompositions comprising, as active ingredient, a compound according tothe invention.

These pharmaceutical compositons are particularly intended for treatingdiabetes, pathological conditions due to the formation of AGEs, such as,in particular, renal complications, atherosclerosis, angiopathy,Alzheimer's disease, neurodegenerative diseases and senility.

The pharmaceutical compounds according to the invention may be providedin forms intended for administration by the parenteral, oral, rectal,permucosal or percutaneous route.

They will therefore be provided in the form of injectable solutions orsuspensions or multidose vials, in the form of uncoated or coatedtablets, sugar-coated tablets, capsules, gelatin capsules, pills,cachets, powders, suppositories or rectal capsules, solutions orsuspensions, for percutaneous use in a polar solvent, for permucosaluse.

The excipients which are suitable for such administrations are thederivatives of cellulose or of microcrystalline cellulose, thealkaline-earth carbonates, magnesium phosphate, starches, modifiedstarches, lactose for the solid forms.

For rectal use, cocoa butter or the stearates of polyethylene glycol arethe preferred excipients.

For parenteral use, water, aqueous solutions, physiological saline,isotonic solutions are the vehicles most conveniently used.

The dosage may vary within wide limits (0.5 mg to 1 000 mg) according tothe therapeutic indication and the route of administration, as well asthe age and weight of the subject.

By way of example, here are a few biguanides of formula II used in thesynthesis of derivatives of formula I.

TABLE I m.p. in Formula Salt ° C. (Köfler) A

HCl 223-225 B

HCl 176-178 C

HCl 230-232 D

HCl 210-212 E

HCl 254-256 F

HCl 158-160 G

HCl 100-102

The following examples illustrate the preparation of the compounds offormula I.

EXAMPLE 1 Synthesis of2-amino-3,6-dihydro-4-dimethylamino-6-ethyl-1,3,5-triazine hydrochloride

23 ml of propionaldehyde and 3.6 g of camphorsulphonic acid are added toa solution of compound A (25.7 g; 0.155 mol) in 200 ml of DMF. Afterrefluxing for 2 hours, the solvent is removed under vacuum and 100 ml ofacetonitrile are added. The solid formed is drained and dried (21.9 g;69%).

m.p. =218-220° C. ¹H NMR (DMSO-d6, 200 MHz): 1.10 (t, 3H); 1.80 (m, 2H)3.20 (s, 6H); 4.83 (m, 1H); 7.57 (m, 2H); 8.65 (s, 1H); 8.90 (s, 1H) ¹³CNMR (DMSO-d6, 50 MHz): 6.41 (CH3); 27.59 (CH2); 35.64 (CH3); 60.75 (CH);155.01 (C═N); 156.67 (C═N)

EXAMPLE 2 Synthesis of2,4-bisdimethylamino-3,6-dihydro-6-methyl-1,3,5-triazine hydrochloride

61 ml of acetal and 5 g of camphorsulphonic acid are added to a solutionof compound E (41.10 g; 0.212 mol) in 200 ml of absolute ethanol. Thewhole is heated under reflux for 72 hours and then concentrated. Thecrude material is triturated with acetonitrile and the solid formed isdrained and then recrystallized from acetonitrile. 24 g (51.5%) of asolid are obtained.

m.p. =200-202° C. ¹H NMR (DMSO-d6, 200 MHz): 1.34 (d, 3H); 3.02 (s, 6H)4.72 (m, 1H); 4.83 (m, 1H); 8.80 (s, 2H) ¹³C NMR (DMSO-d6, 50 MHz):22.59 (CH3); 37.76 (CH3); 59.02 (CH); 156.35 (C═N)

The characteristics of these compounds and of other compounds of formulaI are given in Table II below:

TABLE II m.p. in ° C. ¹³C NMR Formula Salt (Köfler) 50.32 MHz 1

HCl 218-220 DMSO-d6 6.41, CH3 27.59, CH2 35.64, 2 CH3 60.75, CH 155.01,156.67, 2 quaternary C 2

HCl 200-202 DMSO-d6 22.58, 37.75, 5 CH3 59.01, CH 156.34, 2 quaternary C3

193-195 DMSO-d6 32.06, 37.40, 2 CH3 67.85, 158.16, 3 quaternary C 4

HCl 243-245 DMSO-d6 21.66, 25.19, 37.72, 3 CH2 37.89, 2 CH3 67.51,156.83, 158.24, 3 quaternary C 5

Methane- sulphonate 174-176 DMSO-d6 34.31, 41.36, 44.79, 5 CH3 69.75,160.30, 161.44, 3 quaternary C 6

138-140 DMSO-d6 28.04, CH2 30.84, 37.40, 3 CH3 42.06, 62.24, 2 CH270.00, 158.24, 158.69, 3 quaternary C 7

HCl 150-152 DMSO-d6 27.39, CH2 28.78, 39.14, 3 CH3 40.21, 61.30, 2 CH268.46, 156.48, 157.84 3 quaternary C 8

HCl 124-126 DMSO 28.95, 38.65, 2 CH3 42.77, CH2 69.75, quaternary C115.93, CH2 149.12, CH 155.70, 156.16, 2 quaternary C 9

HCl 149-151 DMSO-d6 26.20, 32.39, 40.73, 6 CH3 46.16, CH 60.09, 158.83,159.14, 3 quaternary C 10

HCl 239-241 DMSO-d6 37.78, 2 CH3 62.39, CH 126.66, 129.47, 5 CH 141.87,156.52, 158.38, 3 quaternary C 11

HCl 221-223 DMSO-d6 37.23, 55.60, 3 CH3 61.88, CH 114.32, 127.66, 4 CH133.17, 156.11, 157.86, 159.93, 4 quaternary C 12

HCl 251-253 DMSO-d6 37.75, 2 CH3 62.67, 116.16, 128.16, 5 CH 131.72,156.64, 158.31, 158.88, 4 quaternary C 13

>260 DMSO-d6 39.55, 39.71, 2 CH3 65.92, 117.71, 130.17, 5 CH 131.72,156.64, 158.31, 158.88, 4 quaternary C 14

Fumarate 172-174 15.48, 29.33, 3 CH3 35.68, CH2 37.43, 2 CH3 65.71,quaternary C 135.47, 2 CH 156.21, 156.63, 168.35, 4 quaternary C 15

HCl 250-252 DMSO-d6 28.74, 37.38, 6 CH3 66.53, 155.28, 3 quaternary C 16

HCl 183-185 DMSO-d6 32.62, 40.96, 5 CH3 69.37, 159.30, 160.19, 3quaternary C 17

HCl >260 DMSO-d6 22.78, 2 CH3 28.96, 2 CH2 40.13, 2 CH3 42.73, 2 CH265.63, 155.42, 155.71, 3 quaternary C 18

HCl 229-231 DMSO-d6 22.97, 37.76, 3 CH3 58.59, CH 157.85, 159.39, 2quaternary C 19

HCl >260 Concise spectrum DMSO-d6 69.06, 159.78, 161.17, 3 quaternary C20

carbonate 170-180 CF3CO2D 22.43, 25.71, 36.86, 38.71, 43.12, 7 CH267.88, quaternary C 127.47, 129.55, 129.93, 5 CH 140.22, 158.72, 159.65,3 quaternary C 21

Carbonate >140 DMSO-d6 20.51, CH3 24.73, 25.39, 2 CH2 39.98, 2 CH346.44, 47.91, 2 CH2 58.49, CH 154.58, 156.63, 160.61, 3 quaternary C 22

HCl >260 DMSO-d6 21.18, 24.68, 3 CH2 27.26, CH3 37.00, 2 CH2 37.37, 2CH3 67.12, 155.89, 156.86, 3 quaternary C 23

HCl 248-250 DMSO-d6 15.11, CH3 21.17, 24.70, 35.39, 37.04, 6 CH2 37.36,2 CH3 67.09, 155.90, 156.21, 3 quaternary C 24

HCl >260 Concise spectrum DMSO-d6 67.46, 68.80, 156.76, 157.47, 157.99,159.14, 3 quaternary C 175.90, 176.11, COOH 25

HCl >260 Concise spectrum DMSO-d6 64.87, 69.85, 2 CHOH 66.55, 154.91,156.19, 3 quaternary C 173.75, COOH 26

HCl 91—93 DMSO-d6 25.76, 37.28, 3 CH3 43.28, CH2 64.27, CH 115.21, CH2137.55, CH 159.79, 160.77, 2 quaternary C 27

HCl >260 DMSO-d6 25.69, 27.25, 4 CH2 39.13, 2 CH3 67.25, quaternary C70.01, CH2 72.50, CH 128.17, 128.34, 129.07, 5 CH 139.79, 156.81,158.30, 3 quaternary C 28

HCl >250 DMSO-d6 29.83, 34.4, 4 CH2 38.83, 2 CH3 66.17, CH 67.06,156.25, 157.28, 3 quaternary C 29

Carbonate 133-135 DMSO-d6 7.25, 26.81, 2 CH3 34.32, CH2 37.17, 2 CH368.59, 156.46, 157.71, 160.78, 4 quaternary C 30

Carbonate 140-144 8.68, 2 CH3 34.54, 2 CH2 37.91, 2 CH3 74.98, 157.84,159.14, 160.82, 4 quaternary C 31

HCl 207-209 DMSO-d6 22.50, 2 CH2 38.00, 2 CH3 39.78, 2 CH2 75.51,157.18, 158.37, 3 quaternary C 32

Carbonate decomposes DMSO-d6 14.55, CH3 17.20, CH2 37.45, 2 CH3 39.00,CH2 62.43, CH 157.52, 159.04, 160.65, 3 quaternary C 33

HCl >260 D2O 37.90, 2 CH3 48.69, CH2 154.82, 156.33, 2 quaternary C 34

Para- toluene- sulphonate 201-203 DMSO-d6 21.65, CH3 25.95, 26.07,26.58, 26.89, 27.50, 5 CH2 37.56, 2 CH3 44.74, 66.56, 126.32, 129.08, 6CH 138.99, 145.86, 158.18, 156.86, 4 quaternary C 35

HCl 157-159 DMSO-d6 29.10, 37.86, 4 CH3 65.90, 154.82, 156.33, 3quaternary C 36

Para- toluene- sulphonate 251-253 DMSO-d6 21.14, 37.26, 3 CH3 114.80,120.70, 126.41, 132.12, CF3 125.82, 128.54, 4 CH 138.37, 145.49, 155.78,157.18, 4 quaternary C 37

Para- toluene- sulphonate 159-161 DMSO-d6 21.17, 36.95, 3 CH3 42.60, CH262.10, 126.86, 127.21, 128.55, 128.63, 130.32, 10 CH 135.14, 138.30,145.67, 156.18, 157.44, 5 quaternary C 38

HCl >260 DMSO-d6 37.41, 2 CH3 37.47, 62.73, 4 CH2 64.76, 156.35, 157.77,3 quaternary C 39

HCl >260 DMSO-d6 34.12, 2 CH2 38.63, 42.60, 3 CH3 48.72, 2 CH2 64.01,156.11, 157.78, 3 quaternary C 40

HCl 225-227 DMSO-d6 37.19, 2 CH3 56.58, 107.94, 110.93, 144.00, 4 CH152.78, 155.85, 157.47, 3 quaternary C 41

Para- toluene- sulphonate 194-196 DMSO-d6 21.17, 37.03, 3 CH3 60.37, CH70.05, CH2 115.08, 121.60, 125.84, 128.54, 129.95, 10 CH 138.28, 145.64,156.40, 157.70, 158.45, 5 quaternary C 42

HCl >260 DMSO-d6 24.12, 37.15, 5 CH3 39.90, quaternary C 68.39, CH156.57, 158.10, 2 quaternary C 43

HCl decomposes DMSO-d6 22.95, 23.05, 2 CH3 25.87, CH 36.94, 2 CH3 45.71,CH2 62.38, CH 157.15, 157.42, 158.34, 3 quaternary C 44

HCl 213-215 DMSO-d6 15.99, 17.12, 2 CH3 34.57, CH 37.17, 2 CH3 65.68, CH156.45, 158.12, 2 quaternary C 45

Para- toluene- sulphonate 217-219 DMSO-d6 21.17, CH3 22.53, 24.48,25.30, 3 CH2 37.20, 2 CH3 40.07, 64.37, 2 CH 125.68, 125.83, 127.19,128.61, 6 CH 138.53, 145.24, 156.06, 157.36, 4 quaternary C

Results of pharmacological studies will be given below.

Study of the Antidiabetic Activity in the Nostz Rat

The antidiabetic activity of the compounds of formula (I) administeredorally was determined on an experimental model of non-insulin-dependentdiabetes induced in rats by Streptozotocin.

The non-insulin-dependent diabetes model is obtained in rats by neonatalinjection (on the day of birth) of streptozotocin.

The diabetic rats used were 8 weeks old. The animals were kept, from theday of their birth to the day of the experiment, in an animal house at acontrolled temperature of 21 to 22° C. and subjected to a fixed cycle oflight (from 7 am to 7 pm) and darkness (from 7 pm to 7 am). Their dietconsisted of a maintenance diet, water and food were provided “ablibitum”, with the exception of the 2 hours of fasting preceding thetests when the food is withdrawn (postabsorptive state).

The rats were treated by the oral route for one (D1) or four (D4) dayswith the product to be tested. Two hours after the last administrationof the product and 30 minutes after anaesthetizing the animals withsodium pentobarbital (Nembutal®), 300 μl of blood sample are collectedfrom the end of the tail.

By way of example, results obtained are assembled in Table III. Theseresults show the efficacy of the compounds of formula (I) in reducingglycaemia in the diabetic animals. These results are expressed as apercentage variation of glycaemia at D1 and D4 (number of days oftreatment) relative to D0 (before the treatment).

TABLE III 20 mg/kg/D 200 mg/kg/D Compounds D1 D4 D1 D4  1 −7 −2 −13 −15 2 −11 −10 −12 −12  3 −10 −8 −18 −22  4 0 −1 −20 −10  7 −8 −11 −10 −1615 −8 −9 −4 −5 17 −12 −8 −8 −14 18 −6 −4 −29 −28 19 −10 −6 −4 −14 21 −7−2 −21 −24 22 −23 −16 −13 0 25 −4 −11 −7 −6 26 −6 −11 −14 −9 27 −14 −9−12 −13 28 −4 −1 −4 −13 31 −5 −11 −3 −15 32 2 0 −22 −18 33 −7 −6 −9 −1434 −5 −15 −6 −21 37 −7 −8 −10 −15 39 −6 −6 −4 −7 40 −8 −12 −18 −18 42 −5−4 −26 −17 43 −4 −16 −12 −17 44 −7 −6 −22 −25Study of the Antiglycation Activity

The compounds (1) are also capable of inhibiting the so-called Maillardreactions by “capturing effect” on the α-dicarbonyl-containingderivatives such as glyoxal—this is the antiglycation effect. ThisMaillard reaction inhibiting effect of the compounds according to theinvention was studied in vitro by assaying ketamines (“fructosamines”)produced during the incubation of albumin with methylglyoxal in thepresence or otherwise of a compound of formula (I) according to theinvention.

A solution of bovine albumin at 6.6 mg/ml in 0.2 M phosphate buffer, pH7.4, is incubated with 1 mM methylglyoxal in the presence or otherwiseof a compound according to the invention at a concentration of 10 mM.The incubation is carried out under sterile conditions at 37° C. for 6days. At the end of the incubation period, the quantity of ketamines ismeasured with a commercially available fructosamine assay kit (“FRA”kit, product reference: 0757055, Roche S. A. products) according to themanufacturer's instructions.

By way of example, results obtained under these experimental conditionsare assembled in Table IV: level of fructosamine after incubation of thealbumin with the methylglyoxal in the presence of compounds (I)according to the invention in relation to the level of fructosamine whenalbumin is incubated with methylglyoxal in the absence of the compounds(I) according to the invention.

TABLE IV Reduction in the level of Compounds (I) fructosamines (%)  1 6210 80 11 89 12 90 13 95 18 69 33 79 34 64 36 66 37 65 40 66 43 68 45 67

1. A compound of general formula (I):

in which: R1, R2, are chosen independently from the groups: H, (C1-C20)alkyl wherein R3, R4, are chosen independently from the groups: H₁ (C₁-C₂₀) alkyl (C₂-C₂₀) alkenyl R3 and R4 can form with the nitrogen atom an n-membered ring (n between 3 and 8) optionally comprising one or more heteroatoms chosen from N, O, S, R5 and R6 are chosen independently from the groups: H, (C1-C20)alkyl optionally substituted with hydroxyl, (C3-C8)cycloalkyl optionally substituted with (C6-C14)aryl (C1-C5) alkoxy, (C3-C8)heterocycloalkyl carrying one or more heteroatoms chosen from N, O, S, (C6-C14)aryl optionally substituted with hydroxyl, (C1-C13)heteroaryl carrying one or more heteroatoms chosen from N, O, S, (C6-C14) aryl (C1-C5)alkyl, wherein R5 and R6 can form with the carbon atom to which they are attached an m-membered ring (m between 3 and 8 ) optionally comprising one or more heteroatoms chosen from N, O, S and being capable of being substituted with hydroxyl, (C1-C5)alkyl, (C6-C14)aryl (C1-C5)alkoxy, wherein when R1 and R2 represent a hydrogen, or R3 and R4 represent a hydrogen, then R3 and R4 or R1 and R2 are defined as above with the exception of hydrogen, or its tautomeric, enantiomeric, diastereoisomeric and epimeric form or the pharmaceutically acceptable salt thereof.
 2. The compound of formula (I) according to claim 1, in which R5 is hydrogen.
 3. The compound of formula (I) according to claim 1, in which R5 and R6 form with the carbon atom to which they are attached an m-membered ring (m between 3 and 8 ) optionally comprising one or more heteroatoms chosen from N, O, S and which can be (C1-C5)alkyl.
 4. The compound of formula (I) according to claim 1, in which R5 is a (C2-C20)alkyl group substituted with hydroxyl.
 5. The compound of formula (I) according to claim 1, in which R5 and R6 are chosen from (C1-C20)alkyl groups optionally substituted with hydroxyl.
 6. The compound of formula (I) according to claim 1 in which R1 and R2 are chosen independently from the groups specified in claim 1 with the exception of the hydrogen atom and R3 and R4 represent a hydrogen.
 7. The compound of formula (I) according to claim 6, in which R1 and R2 are a methyl group and R3 and R4 represent a hydrogen.
 8. The method for preparing a compound according to claim 1 comprising reacting a compound of general formula (II)

in which R1, R2, R3 and R4 are as defined above, with a compound of general formula (III), (IV) or (V)

in which R5 and R6 are as defined above and R7 is a methyl or ethyl group, in a polar solvent in the presence of an organic or inorganic acid.
 9. A pharmaceutical composition comprising, as active ingredient, therapeutically effective amount of a compound according to claim
 1. 10. A method for the treatment of diabetes comprising administering to a patient in need thereof an effective amount of a compound according to claim
 1. 11. A method for treating pathological conditions selected from the group consisting of dyslilpidaemia, obesity, high blood pressure, atherosclerosis, retinopathies and neuropathies, comprising administering to a patient in the need thereof an effective amount of a compound according to claim
 1. 